线粒体电子传递链在细胞增殖中的重要作用是促进天冬氨酸的合成。
An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis.
作者信息
Birsoy Kıvanç, Wang Tim, Chen Walter W, Freinkman Elizaveta, Abu-Remaileh Monther, Sabatini David M
机构信息
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA.
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
出版信息
Cell. 2015 Jul 30;162(3):540-51. doi: 10.1016/j.cell.2015.07.016.
The mitochondrial electron transport chain (ETC) enables many metabolic processes, but why its inhibition suppresses cell proliferation is unclear. It is also not well understood why pyruvate supplementation allows cells lacking ETC function to proliferate. We used a CRISPR-based genetic screen to identify genes whose loss sensitizes human cells to phenformin, a complex I inhibitor. The screen yielded GOT1, the cytosolic aspartate aminotransferase, loss of which kills cells upon ETC inhibition. GOT1 normally consumes aspartate to transfer electrons into mitochondria, but, upon ETC inhibition, it reverses to generate aspartate in the cytosol, which partially compensates for the loss of mitochondrial aspartate synthesis. Pyruvate stimulates aspartate synthesis in a GOT1-dependent fashion, which is required for pyruvate to rescue proliferation of cells with ETC dysfunction. Aspartate supplementation or overexpression of an aspartate transporter allows cells without ETC activity to proliferate. Thus, enabling aspartate synthesis is an essential role of the ETC in cell proliferation.
线粒体电子传递链（ETC）支持多种代谢过程，但目前尚不清楚其受到抑制为何会抑制细胞增殖。丙酮酸补充剂能使缺乏ETC功能的细胞增殖，其原因也未得到充分理解。我们利用基于CRISPR的基因筛选来鉴定那些缺失会使人细胞对苯乙双胍（一种复合体I抑制剂）敏感的基因。筛选结果得到了GOT1（胞质天冬氨酸转氨酶），其缺失会在ETC受抑制时导致细胞死亡。GOT1通常消耗天冬氨酸以将电子转运至线粒体，但在ETC受抑制时，它会逆转以在胞质中生成天冬氨酸，这部分补偿了线粒体天冬氨酸合成的损失。丙酮酸以依赖GOT1的方式刺激天冬氨酸合成，这是丙酮酸挽救ETC功能障碍细胞增殖所必需的。补充天冬氨酸或过表达天冬氨酸转运体可使无ETC活性的细胞增殖。因此，使天冬氨酸合成得以进行是ETC在细胞增殖中的一项重要作用。
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